Adenoviral vectors have been broadly used in cancer gene therapy but their utility has been limited by the insufficient transduction levels achieved. One factor that contributes to this limitation is the poor infectability of primary tumors due to low levels of the primary adenovirus receptor CAR. As a possible solution to this problem, our group has developed methods to increase adenovirus infectivity based on the modification of the virus tropism. We have demonstrated that the modification of the adenovirus fiber by genetic manipulation increases infectivity of primary tumors several orders of magnitude by the achievement of CAR-independent gene transfer. As a different solution, conditional replicative adenoviruses that propagate selectively in tumors have been used to achieve extensive lysis and transduction of tumors. For this replicative viruses is important to achieve tumor-selective replication to reduce their toxicity. Our group has developed methods of specific trans-complementation of replication defective adenoviral vectors cased on co-delivery of plasmids that enable replication. Using these methods we have achieved replication of viruses defective in essential early regions E1 and E4. It is our hypothesis that improving the infectivity and specificity of conditional replicative vectors will improve their therapeutic efficacy. We intend to modify the fiber of replicative adenovirus with an RGD motif that binds to integrins. This will provide an additional infectivity pathway different from the natural adenovirus receptor. In a second part of this project, we intend to combine this fiber modification with new methods to achieve tumor-selective replication on the transcriptional control of E4 or/and E2. Finally, we intend to demonstrate the oncolytic efficacy of these enhanced-infectability tumor- selective adenoviruses in murine models.